ACS Chem Biol. 2021 Jan 15;16(1):14-19. doi: 10.1021/acschembio.0c00716. Epub 2021 Jan 5.
-GlcNAc modification of the microtubule associated protein tau and α-synuclein can directly inhibit the formation of the associated amyloid fibers associated with major classes of neurodegenerative diseases. However, the mechanism(s) by which this posttranslational modification (PTM) inhibit amyloid aggregation are still murky. One hypothesis is that -GlcNAc simply acts as a polyhydroxylated steric impediment to the formation of amyloid oligomers and fibers. Here, we begin to test this hypothesis by comparing the effects of -GlcNAc to other similar monosaccharides-glucose, -acetyl-galactosamine (GalNAc), or mannose-on α-synuclein amyloid formation. Interestingly, we find that this quite reasonable hypothesis is not entirely correct. More specifically, we used four types of biochemical and biophysical assays to discover that the different sugars display different effects on the inhibition of amyloid formation, despite only small differences between the structures of the monosaccharides. These results further support a more detailed investigation into the mechanism of amyloid inhibition by -GlcNAc and has potential implications for the evolution of -acetyl-glucosamine as the monosaccharide of choice for widespread intracellular glycosylation.
糖基化修饰的微管相关蛋白 tau 和 α-突触核蛋白可以直接抑制与主要神经退行性疾病相关的淀粉样纤维的形成。然而，这种翻译后修饰（PTM）抑制淀粉样聚集的机制尚不清楚。一种假设是 GlcNAc 只是作为一种多羟基的空间位阻物，阻止淀粉样寡聚体和纤维的形成。在这里，我们通过比较 GlcNAc 与其他类似单糖（葡萄糖、N-乙酰半乳糖胺（GalNAc）或甘露糖）对 α-突触核蛋白淀粉样形成的影响来开始检验这一假说。有趣的是，我们发现这个相当合理的假设并不完全正确。更具体地说，我们使用了四种生化和生物物理测定方法来发现，尽管单糖的结构只有微小差异，但不同的糖对抑制淀粉样形成的影响不同。这些结果进一步支持了对 GlcNAc 抑制淀粉样形成机制的更详细研究，并可能对 N-乙酰葡萄糖胺作为广泛细胞内糖基化选择的单糖的进化产生影响。
